Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia

By J. Byrd, R. Furman, S. Coutre, I. Flinn, J. Burger, K. Blum, B. Grant, J. Sharman, M. Coleman, W. Wierda and 11 more. New England Journal of Medicine, 2013

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BACKGROUND The treatment of relapsed chronic lymphocytic leukemia (CLL) has resulted in few durable remissions. Bruton's tyrosine kinase (BTK), an essential component of B-cell–receptor signaling, mediates interactions with the tumor microenvironment and promotes the survival and proliferation of CLL cells. METHODS We conducted a phase 1b–2 multicenter study to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of ibrutinib (PCI-32765), a first-in-class, oral covalent inhibitor of BTK designed for treatment of B-cell cancers, in patients with relapsed or refractory CLL or small lymphocytic lymphoma. A total of 85 patients, the majority of whom were considered to have high-risk disease, received ibrutinib orally once daily; 51 received 420 mg, and 34 received 840 mg. RESULTS Toxic effects were predominantly grade 1 or 2 and included transient diarrhea, fatigue, and upper respiratory tract infection; thus, patients could receive extended treatment with minimal hematologic toxic effects. The overall response rate was the same in the group that received 420 mg and the group that received 840 mg (71%), and an additional 20% and 15% of patients in the respective groups had a partial response with lymphocytosis. The response was independent of clinical and genomic risk factors present before treatment, including advanced-stage disease, the number of previous therapies, and the 17p13.1 deletion. At 26 months, the estimated progression-free survival rate was 75% and the rate of overall survival was 83%. CONCLUSIONS Ibrutinib was associated with a high frequency of durable remissions in patients with relapsed or refractory CLL and small lymphocytic lymphoma, including patients with high-risk genetic lesions. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01105247.)

Subfields: Genetics, Immunology, Oncology

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Citations in the corpus

Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents. (2015, background): “Ibrutinib is an irreversible inhibitor of Bruton agammaglobulinemia tyrosine kinase (BTK) approved for the treatment of mantle cell lymphoma and chronic lymphocytic leukemia (Byrd et al., 2013; Wang et al., 2013).”
Role of Bruton’s tyrosine kinase in B cells and malignancies (2018, background): “R/R CLL Ibrutinib Ib/II ORR (71%), PR(20%) [11]”
Ibrutinib versus Ofatumumab in Previously Treated Chronic Lymphoid Leukemia (2014, neutral): “Peripheral sensory neuropathy 8 (4) 0 24 (13) 0”
Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. (2015, neutral): “Median platelets, 3 10(9)/L (range) 113 (32-217) 105 (2-310) 105 (2-310) #100 3 10(9)/L, n (%) 12 (39) 49 (49) 61 (46)”
Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia. (2014, result): “These results appear similar to those reported recently with the BTK inhibitor ibrutinib, particularly given that patients in this phase 1 study of idelalisib appeared to have more heavily pretreated and refractory disease than those treated in the phase 2 study of ibrutinib.(25) Although the PFS of”